standard-title Common Chromosomal Abnormalities

Common Chromosomal Abnormalities

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 21, one copy inherited from each parent, form one of the pairs. Chromosome 21 is the smallest human chromosome, spanning about 47 million base pairs (the building blocks of DNA) and representing approximately 1.5 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 21?

The following conditions are caused by changes in the structure or number of copies of chromosome 21.

  • Down syndrome

Down syndrome is most often caused by trisomy 21. Trisomy 21 means that each cell in the body has three copies of chromosome 21 instead of the usual two copies. Down syndrome can also result from an extra copy of chromosome 21 in only some of the body’s cells (mosaic Down syndrome). Down syndrome occurs in 1 in 800 to 1,000 births.

In a small percentage of cases, Down syndrome is caused by a rearrangement of chromosomal material between chromosome 21 and another chromosome. As a result, a person has the usual two copies of chromosome 21, plus extra material from chromosome 21 attached to another chromosome. These cases are called translocation Down syndrome.

Researchers believe that extra copies of genes on chromosome 21 disrupt the course of normal development, causing the characteristic features of Down syndrome and the increased risk of medical problems associated with this disorder.

Down syndrome is associated with mental retardation, a characteristic facial appearance, and poor muscle tone (hypotonia) in infancy. People with this condition are at an increased risk for heart defects, digestive problems such as gastroesophageal reflux or celiac disease, hearing loss, and cancer of blood-forming tissue (leukemia). Additionally, some people with Down syndrome have reduced activity of the thyroid gland (hypothyroidism). The thyroid gland is a butterfly-shaped organ in the lower neck that produces hormones. Some evidence indicates that Down syndrome is associated with an increased risk of Alzheimer disease, a degenerative disease of the brain that causes a gradual loss of memory, judgment, and ability to function. Although Alzheimer disease is usually a disorder of late adulthood, in people with Down syndrome the signs and symptoms can appear as early as age 30.

  • Cancers

Rearrangements (translocations) of genetic material between chromosome 21 and other chromosomes have been associated with several types of cancer. For example, acute lymphoblastic leukemia (a type of blood cancer most often diagnosed in childhood) has been associated with a translocation between chromosomes 12 and 21. Another form of leukemia, acute myeloid leukemia, has been associated with a
translocation between chromosomes 8 and 21.

  • Other chromosomal conditions

Other changes in the number or structure of chromosome 21 can have a variety of effects, including mental retardation, delayed development, and characteristic facial features. In some cases, the signs and symptoms are similar to those of Down syndrome. Changes to chromosome 21 include a missing segment of the chromosome in each cell (partial monosomy 21) and a circular structure called ring chromosome 21. A ring chromosome occurs when both ends of a broken chromosome are reunited.

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 13, one copy inherited from each parent, form one of the pairs. Chromosome 13 spans about 114 million base pairs (the building blocks of DNA) and represents between 3.5 percent and 4 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 13?

The following conditions are caused by changes in the structure or number of copies of chromosome 13.

  • Trisomy 13 (Patau syndrome)

Trisomy 13 occurs when each cell in the body has three copies of chromosome 13 instead of the usual two copies. Trisomy 13 can also result from an extra copy of chromosome 13 in only some of the body’s cells (mosaic trisomy 13).

In a small percentage of cases, trisomy 13 is caused by a rearrangement of chromosomal material between chromosome 13 and another chromosome. As a result, a person has the two usual copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. These cases are called translocation trisomy 13.

Extra material from chromosome 13 disrupts the course of normal development, causing the characteristic signs and symptoms of trisomy 13. Researchers have not determined how this extra genetic material leads to the features of the disorder.

Patau syndrome is associated with severe mental retardation and certain physical abnormalities. These abnormalities include small eyes that may exhibit a split in the iris (coloboma), an opening in the roof of the mouth (a cleft palate) and/or a cleft lip, weak muscle tone (hypotonia), skeletal abnormalities, an increased risk of heart defects, and other medical problems. Affected individuals rarely live past infancy because of the life-threatening medical problems associated with this condition.

Most cases of trisomy 13 are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of chromosome 13. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each cell of the body.

Mosaic trisomy 13 is also not inherited. It occurs as a random error during cell division early in fetal development. As a result, some of the body’s cells have the usual two copies of chromosome 13, and other cells have three copies of the chromosome.

Translocation trisomy 13 can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of trisomy 13, people who carry this type of balanced translocation are at an increased risk of having children with the condition.

  • Retinoblastoma

Retinoblastoma is a rare type of eye cancer that develops in the retina, the part of the eye that detects light and color. Although this disorder can occur at any age, it usually develops in young children. People with the hereditary form of retinoblastoma may also develop a tumor in the brain called pinealoma. Later in life, people with hereditary retinoblastoma also have an increased risk of developing bone cancer (osteosarcoma), soft tissue cancers, a form of skin cancer called melanoma, and other types of cancer. Retinoblastoma affects an estimated 1 in 15,000 to 20,000 live births. It accounts for about 3 percent of all cancers in children younger than 15 years.

A small percentage of retinoblastoma cases are caused by deletions in the region of chromosome 13 (13q14) containing the RB1 gene. Children with these chromosomal deletions may also have mental retardation, slow growth, and characteristic facial features (such as prominent eyebrows, a broad nasal bridge, a short nose, and ear abnormalities). Researchers have not determined which other genes are located in the deleted region, but a loss of several genes is likely responsible for these developmental problems. Mutations in the RB1 gene are inherited in an autosomal dominant pattern,
which means that one copy of the altered gene in each cell is sufficient to increase cancer risk. A person with retinoblastoma may inherit an altered copy of the gene from one parent, or the altered gene may be the result of a new mutation. For retinoblastoma to develop, a second mutation in the other copy of the RB1 gene must occur in retinal cells during the person’s lifetime. The small number of retinoblastoma cases caused by chromosome 13 deletions are usually not inherited. These chromosomal changes occur as random events during the formation of reproductive cells (eggs and sperm) or during cell division early in fetal development.

  • Other chromosomal conditions

Partial monosomy 13q is a rare chromosomal disorder that results when a piece of the long arm (q) of chromosome 13 is missing (monosomic). Infants born with partial monosomy 13q may exhibit low birth weight, malformations of the head and face (craniofacial region), skeletal abnormalities (especially of the hands and feet), and other physical abnormalities. Mental retardation is characteristic of this condition. The mortality rate during infancy is high among individuals born with this disorder. Almost all cases of partial monosomy 13q occur randomly for no apparent reason (sporadic).

The X chromosome is one of the two sex chromosomes in humans (the other is the Y chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The X chromosome spans about 155 million base pairs (the building blocks of DNA) and represents approximately 5 percent of the total DNA in cells. The Y chromosome spans about 58 million base pairs (the building blocks of DNA) and represents almost 2 percent of the total DNA in cells.

Each person normally has one pair of sex chromosomes in each cell. The Y chromosome is present in males, who have one X and one Y chromosome, while females have two X chromosomes.

What chromosomal conditions are related to the X chromosome?

The following conditions are caused by changes in the structure or number of copies of the X chromosome.

  • Turner syndrome (XO Syndrome)

Turner syndrome results when each of a female’s cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the characteristic features of the condition, including short stature, learning problems, and inability to conceive a child (infertility) because of an absence of ovarian function. Other features of Turner syndrome can include extra skin on the neck (webbed neck), puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, heart defects, and kidney problems. Developmental delays, learning disabilities, and behavioral problems are also possible, although these characteristics vary among affected females.Turner syndrome affect about 1 in every 2000 girls born in Australia.

About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in an individual’s body has only one copy of the X chromosome instead of the usual two sex chromosomes. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely missing.

Some people with Turner syndrome have a chromosomal change in only some of their cells. Some cells have the usual two sex chromosomes (either two X chromosomes or one X chromosome and one Y chromosome), and other cells have only one copy of the X chromosome. These cases are called Turner syndrome mosaics (45,X/46,XX or 45,X/46,XY).

Most cases of turner syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called non disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may
lose a sex chromosome as a result of non disjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have a single X chromosome in each cell and will be missing the other sex chromosome.

X-chromosome mosaicism is also not inherited. It occurs as a random error during cell division in early fetal development. As a result, some of an affected person’s cells have the usual two sex chromosomes (either two X chromosomes or one X chromosome and one Y chromosome), and other cells have only one copy of the X chromosome.

  • Triple X syndrome

Triple X syndrome (also called 47,XXX or trisomy X) results from an extra copy of the X chromosome in each of a female’s cells. Most often, this chromosomal change causes no unusual physical features or medical problems. Females with triple X syndrome are sometimes taller than average and have an increased risk of learning disabilities and delayed speech and language skills. Developmental delays and behavioral problems are also possible, but these characteristics vary widely among affected girls and women. Most females with triple X syndrome have normal sexual development and are able to conceive children. This condition occurs in about 1 in 1,000 newborn girls. Five to 10 girls with triple X syndrome are born in the United States each day.

Females with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. It remains uncertain why an extra copy of the X chromosome is associated with tall stature and learning problems in some girls and women.

Females with more than one extra copy of the X chromosome (48,XXXX or 49,XXXXX) have been identified, but these conditions are rare. The extra genetic material may lead to mental retardation and other medical problems.

Trisomy X usually is not inherited, but occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a female child, the child will have an extra X chromosome in each of the body’s cells.

In some cases, trisomy X results from nondisjunction during cell division in early embryonic development. These cases are usually 46,XX/47,XXX mosaics.

  • Other chromosomal conditions

Chromosomal conditions involving the sex chromosomes often affect sex determination (whether a person has the sexual characteristics of a male or a female), sexual development, and the ability to have children (fertility). The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in the chromosomes.

What chromosomal conditions are related to the Y chromosome?

The following conditions are caused by changes in the structure or number of copies of the Y chromosome.

  • Klinefelter syndrome (XXY Syndrome)

Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male’s cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone. A lack of this hormone can lead to breast development (gynecomastia) which lead to an increased risk of developing breast cancer. Klinefelter syndrome affects between 1 in 500 to1000 males born each year in
Australia.

Typically, males with Klinefelter syndrome have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). Less commonly, affected males may have two or three extra X chromosomes (48,XXXY or 49,XXXXY) or extra copies of both the X and Y chromosomes (48,XXYY) in each cell. The extra genetic material disrupt normal sexual development and may lead to mental retardation and other medical problems. The range and severity of symptoms depends on the number and distribution of cells containing the extra copy of the X chromosome. The most common features include learning disabilities include difficulties with speech and language development and a tendency to grow at a slightly quicker rate than their peers so that their final height may be more than expected, but is usually within the normal range; reduction in body hair, beard growth and testicular size that can be treated with the male hormone testosterone; while sexuality is normal although men with the syndrome may be infertile.

Klinefelter syndrome can also result from an extra X chromosome in only some of the body’s cells. These cases are called mosaic 46,XY/47,XXY.

Klinefelter syndrome is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or several extra X chromosomes in each of the body’s cells.

Mosaic 46,XY/47,XXY occurs as a random error during cell division early in fetal development. As a result of this error, some cells have one X chromosome and one Y chromosome (46,XY), and other cells have an extra copy of the X chromosome (47,XXY).

  • 47,XYY syndrome

47,XYY syndrome is caused by the presence of a single extra copy of the Y chromosome in each of a male’s cells. Males with 47,XYY syndrome have one X chromosome and two Y chromosomes, for a total of 47 chromosomes per cell. It remains uncertain why an extra copy of the Y chromosome is associated with tall stature and learning problems in some boys and men.

  • Other chromosomal conditions

Chromosomal conditions involving the sex chromosomes often affect sex determination (whether a person has the sexual characteristics of a male or a female), sexual development, and the ability to have children (fertility). The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in these chromosomes.

Rarely, males may have more than one extra copy of the Y chromosome in every cell (polysomy Y). The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the features of these conditions are variable.

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 15, one copy inherited from each parent, form one of the pairs. Chromosome 15 spans about 100 million base pairs (the building blocks of DNA) and represents more than 3 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 15?

The following conditions are caused by changes in the structure or number of copies of chromosome 15.

  • Angelman syndrome

Angelman syndrome is a complex genetic disorder that affects the nervous system. Characteristic features of this condition include developmental delay or mental retardation, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). Delayed development can be noted by 6 months to 12 months of age, and other common signs and symptoms usually become apparent in early childhood. People with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling and laughter, a short attention span, and hand-flapping movements. Some affected individuals also have unusually fair skin and light-colored hair. Angelman syndrome affects an estimated 1 in 12,000 to 20,000 people.

Angelman syndrome results from a loss of gene activity in a specific part of chromosome 15 (the 15q11-q13 region) in each cell. This region contains a gene called UBE3A that, when mutated or absent, likely causes the characteristic features of this condition. People normally inherit one copy of the UBE3A gene from each parent. Both copies of this gene are active in many of the body’s tissues. In the brain, however, only the copy inherited from a person’s mother (the maternal copy) is active. This parent-specific gene activation is called genomic imprinting. If the maternal copy is lost because of a chromosomal change or a gene mutation, a person will have no working copies of the UBE3A gene in the brain.

In most cases (about 70 percent), people with Angelman syndrome have a deletion in the maternal copy of chromosome 15. This chromosomal change deletes the region of chromosome 15 that includes the UBE3A gene. Because the copy of the UBE3A gene inherited from a person’s father (the paternal copy) is normally inactive in the brain, a deletion in the maternal chromosome 15 leaves no active copies of the UBE3A gene in the brain.

In 3 percent to 7 percent of cases of Angelman syndrome, people inherit two copies of chromosome 15 from their father instead of one copy from each parent. This phenomenon is called paternal uniparental disomy (UPD). People with paternal UPD for chromosome 15 have two copies of the UBE3A gene, but they are both inherited from the father and therefore are inactive in the brain.

About 10 percent of Angelman syndrome cases are caused by a mutation in the UBE3A gene, and another 3 percent result from a defect in the DNA region that controls the activation of the UBE3A gene and other genes on the maternal copy of chromosome 15. In a small percentage of cases, Angelman syndrome may be caused by a chromosomal rearrangement (translocation) or by a mutation in a gene other than UBE3A. These genetic changes can abnormally inactivate the UBE3A gene.

  • Prader-Willi syndrome

Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite and chronic overeating (hyperphagia). As a result, most experience rapid weight gain leading to obesity. People with Prader-Willi syndrome typically have mental retardation or learning disabilities and behavioral problems. Many people with this disorder also have distinctive facial features and short stature. The genitals in both males and females are underdeveloped, and most affected individuals are unable to conceive children (infertile). Additionally, some people with Prader-Willi syndrome have unusually fair skin and light-colored hair. Prader-Willi syndrome affects an estimated 1 in 10,000 to 25,000 people.

Prader-Willi syndrome is caused by the loss of active genes in a specific part of chromosome 15 (the 15q11-q13 region) in each cell. People normally inherit one copy of this chromosome from each parent. Some genes are active only on the copy inherited from a person’s father (the paternal copy). This parent-specific gene activation is called genomic imprinting. Prader-Willi syndrome occurs when the paternal copy of chromosome 15 is partly or entirely missing. Researchers are working to identify genes on this chromosome whose absence is associated with the characteristic features of Prader-Willi syndrome.

In about 70 percent of cases, Prader-Willi syndrome occurs when the 15q11-q13 region of the paternal chromosome 15 is deleted in each cell. A person with a deletion in the paternal chromosome 15 will have no active genes in this region because the genes on the paternal copy are missing and the genes on the maternal copy are inactive.

In about 25 percent of cases, people with Prader-Willi syndrome inherit two copies of chromosome 15 from their mother instead of one copy from each parent. This phenomenon is called maternal uniparental disomy. A person with two maternal copies of chromosome 15 will have no active copies of these genes.

In a small percentage of cases, Prader-Willi syndrome is caused by a chromosomal rearrangement called a translocation. Rarely, the condition results from an abnormality in the DNA region that controls the activity of genes on the paternal chromosome 15.

  • Other chromosomal conditions

A particular chromosomal change called an isodicentric chromosome 15 (previously called an inverted duplication 15) can affect growth and development. This small extra chromosome is made up of genetic material from chromosome 15 that has been abnormally duplicated. In some cases, the extra chromosome is very small and has no effect on a person’s health. A larger isodicentric chromosome 15 can result in weak muscle tone (hypotonia), mental retardation, seizures, and behavioral problems. This chromosomal change also has been found in some children with the features of autism or related developmental disorders affecting communication and social interaction.

Other changes in the number or structure of chromosome 15 can cause mental retardation, delayed growth and development, hypotonia, and characteristic facial features. These changes include an extra copy of part of chromosome 15 in each cell (partial trisomy 15), a missing segment of the chromosome in each cell (partial monosomy 15), and a circular structure called ring chromosome 15. A ring chromosome occurs when both ends of a broken chromosome are reunited.

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 16, one copy inherited from each parent, form one of the pairs. Chromosome 16 spans about 89 million base pairs (the building blocks of DNA) and represents almost 3 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 16?

The following conditions are caused by changes in the structure or number of copies of chromosome 16.

  • Cancers

Changes in the structure of chromosome 16 are associated with several types of cancer. These genetic changes are somatic, which means they are acquired during a person’s lifetime and are present only in certain cells. In some cases, chromosomal rearrangements called translocations disrupt the region of chromosome 16 that contains the CREBBP gene. The protein produced from this gene normally plays a role in regulating cell growth and division, which helps prevent the development of cancers.

Researchers have found a translocation between chromosome 8 and chromosome 16 that disrupts the CREBBP gene in some people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation involving the CREBBP gene, which rearranges pieces of chromosomes 11 and 16, has been found in some people who have undergone cancer treatment. This chromosomal change is associated
with the later development of AML and two other cancers of blood-forming tissues (chronic myelogenous leukemia and myelodysplastic syndrome). These are sometimes described as treatment-related cancers because the translocation between chromosomes 11 and 16 occurs following chemotherapy for other forms of cancer.

Researchers have found a translocation between chromosome 8 and chromosome 16 that disrupts the CREBBP gene in some people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation involving the CREBBP gene, which rearranges pieces of chromosomes 11 and 16, has been found in some people who have undergone cancer treatment. This chromosomal change is associated with the later development of AML and two other cancers of blood-forming tissues (chronic myelogenous leukemia and myelodysplastic syndrome). These are sometimes described as treatment-related cancers because the translocation between chromosomes 11 and 16 occurs following chemotherapy for other forms of cancer.

  • Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome is a condition characterized by short stature, moderate to severe mental retardation, distinctive facial features, and broad thumbs and first toes. Additional features of the disorder can include eye abnormalities, heart and kidney defects, dental problems, and obesity. These
signs and symptoms vary among affected individuals. People with this condition have an increased risk of developing noncancerous and cancerous tumors, including certain kinds of brain tumors. Cancer of blood-forming tissue (leukemia) also occurs more frequently in people with Rubinstein-Taybi syndrome. Rarely, Rubinstein-Taybi syndrome can involve serious complications such as a failure to gain weight and grow at the expected rate (failure to thrive) and life-threatening infections. Infants born with this severe form of the disorder usually survive only into early childhood. This condition is uncommon; it occurs in an estimated 1 in 100,000 to 125,000 newborns.

A few cases of severe Rubinstein-Taybi syndrome (also known as chromosome 16p13.3 deletion syndrome) have resulted from a deletion of genetic material from the short (p) arm of chromosome 16. When this deletion is present in all of the body’s cells, it can cause serious complications such as a failure to gain weight and grow at the expected rate (failure to thrive) and an increased risk of life-threatening infections. Affected individuals also have many of the typical features of Rubinstein-
Taybi syndrome, including mental retardation, distinctive facial features, and broad thumbs and first toes. Infants born with the severe form of this disorder usually survive only into early childhood.

Several genes are missing as a result of the deletion in the short arm of chromosome 16. The deleted region includes the CREBBP gene, which is often mutated or missing in people with the typical features of Rubinstein-Taybi syndrome. Researchers believe that the loss of additional genes in this region probably accounts for the serious complications associated with severe Rubinstein-Taybi syndrome.

  • Other chromosomal conditions

Trisomy 16 occurs when cells have three copies of chromosome 16 instead of the usual two copies. Full trisomy 16, which occurs when all of the body’s cells contain an extra copy of chromosome 16, is not compatible with life. A similar but less severe condition called mosaic trisomy 16 occurs when only some of the body’s cells have an extra copy of chromosome 16. The signs and symptoms of mosaic trisomy 16 vary widely and can include slow growth before birth (intrauterine growth retardation), delayed development, and heart defects.

Other changes in the number or structure of chromosome 16 can have a variety of effects. Mental retardation, delayed growth and development, distinctive facial features, weak muscle tone (hypotonia), heart defects, and other medical problems are common. Frequent changes to chromosome 16
include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 16p or 16q) and a missing segment of the long arm of the chromosome in each cell (partial monosomy 16q).

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 21, one copy inherited from each parent, form one of the pairs. Chromosome 21 is the smallest human chromosome, spanning about 47 million base pairs (the building blocks of DNA) and representing approximately 1.5 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 18?

The following conditions are caused by changes in the structure or number of copies of chromosome 18.

  • Trisomy 18

Trisomy 18, also called Edwards syndrome, is a chromosomal condition that is associated with low birth weight; a small, abnormally shaped head; a small jaw; a small mouth; and clenched fists with overlapping fingers. Infants born with trisomy 18 have mental retardation, heart defects, and organ abnormalities affecting most systems of the body. Affected individuals have an extremely high mortality rate; only 5 percent to 10 percent of infants born with trisomy 18 survive the first year of life. Trisomy 18 affects about 1 in 5,000 to 6,000 newborns. Approximately 80 percent of newborns affected by this disorder are female. The risk of having a child with trisomy 18 increases as a woman gets older.

Trisomy 18 results when each cell in the body has three copies of chromosome 18 instead of the usual two copies. Trisomy 18 can also result from an extra copy of chromosome 18 in only some of the body’s cells (mosaic trisomy 18). Rarely, trisomy 18 is caused by a rearrangement of chromosomal material between chromosome 18 and another chromosome; as a result, a person has the two usual copies of chromosome 18, plus extra material from chromosome 18 attached to another chromosome. These cases are called translocation trisomy 18.

Extra material from chromosome 18 disrupts the course of normal development, causing the characteristic signs and symptoms of trisomy 18. Researchers have not determined how this extra genetic material leads to the features of this disorder.

Most cases of trisomy 18 are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of chromosome 18. Mosaic trisomy 18 is also not inherited. It occurs as a random error during cell division early in fetal development. As a result, some of the body’s cells have the usual two copies of chromosome 18, and other cells have three copies of the chromosome. Translocation
trisomy 18 can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 18 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 18. Although they do not have signs of trisomy 18, people who carry this type of balanced translocation are at an increased risk of having children with the condition.

  • Other chromosomal conditions

Other disorders associated with chromosome 18 occur when pieces of either the long (q) arm or the short (p) arm of this chromosome are missing or when extra genetic material from chromosome 18 is present. Researchers are uncertain how missing or extra pieces of chromosome 18 lead to the features of these disorders.

Chromosome 18p partial monosomy may occur when a piece of the short arm of this chromosome is deleted. Children with this condition are abnormally short and may be developmentally delayed. Serious defects of the brain and spinal cord (central nervous system) are sometimes present. If no serious malformations are present, survival to adulthood is common.

Chromosome 18q partial monosomy also may occur when a piece of the long arm of this chromosome is deleted. Children with this condition are usually shorter than average, have some minor skeletal abnormalities, may have moderate to severe mental retardation, and exhibit movement disorders. Depending on the severity of this disorder, survival to adulthood is possible.

Extra pieces of the short arm of chromosome 18 can result in a disorder called tetrasomy 18p. This disorder occurs when a person has extra material from chromosome 18 called an isochromosome. This isochromosome is made up of two copies of the short arm of chromosome 18 and no copies of the long arm. As a result, cells have four copies of the short arm of chromosome 18 instead of the usual two copies. Children born with this condition are unusually small, developmentally delayed, and may have mild to severe mental retardation. Other features can include low-set ears, a small head (microcephaly), a high arch in the roof of the mouth (high-arched palate), and a small mouth. Depending on the severity of this disorder, survival to adulthood is possible.

In some cases, chromosome 18 breaks at both ends and loses varying amounts of material from each arm. The broken ends are joined to form a circular structure. This chromosome abnormality is called a ring
chromosome 18. Children with a ring chromosome 18 typically have mental retardation, and many also have microcephaly, widely spaced eyes (hypertelorism), low-set ears, and speech problems. These features vary, however, depending on how much genetic material is lost from each arm of the chromosome.

Humans normally have 46 chromosomes (23 pairs) in each cell. Two copies of chromosome 22, one copy inherited from each parent, form one of the pairs. Chromosome 22 is the second smallest human chromosome, spanning about 50 million DNA building blocks (base pairs) and representing between 1.5 percent and 2 percent of the total DNA in cells.

What chromosomal conditions are related to chromosome 22?

The following conditions are caused by changes in the structure or number of copies of chromosome 22.

  • Cancers

A rearrangement (translocation) of genetic material between chromosomes 9 and 22 is associated with several types of blood cancer known as leukemias. This chromosomal abnormality, which is commonly called the Philadelphia chromosome, is found only in cancer cells. It fuses part of a specific gene from chromosome 22 (the BCR gene) with part of another gene from chromosome 9 (the ABL gene). The protein produced from this fused gene abnormally signals tumor cells to continue dividing and prevents
them from adequately repairing DNA damage.

The Philadelphia chromosome has been identified in most cases of a slowly progressing form of blood cancer called chronic myeloid leukemia (CML). It also has been found in some cases of more rapidly progressing blood cancers known as acute leukemias. The presence of the Philadelphia chromosome can help predict how a cancer will progress and provides a target for molecular therapies.

  • 22q11.2 deletion syndrome

Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs on one copy of chromosome 22 in each cell. The deletion occurs near the middle of the chromosome at a location designated as q11.2. This region contains 30 to 40 genes, but many of these genes have not been well
characterized. A small percentage of affected individuals have shorter deletions in the same region.

The loss of a particular gene, TBX1, is thought to be responsible for many of the characteristic features of 22q11.2 deletion syndrome such as heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, and low calcium levels. Some studies suggest that a deletion of this gene may contribute to behavioral problems as well. The loss of another gene, COMT, in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. Additional genes in the deleted region likely contribute to the signs and symptoms of 22q11.2 deletion syndrome.

  • Opitz G/BBB syndrome

Opitz G/BBB syndrome is a genetic condition that affects several structures along the midline of the body. The most common features of this condition are wide-spaced eyes (hypertelorism); defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing (dysphagia); and in males, the urethra opening on the underside of the penis (hypospadias). Mild mental retardation occurs in fewer than 50 percent of people with Opitz G/BBB syndrome, most likely caused by structural
defects in the brain. About half of affected individuals also have cleft lip with or without a cleft palate (an opening in the roof of the mouth). Some have cleft palate alone. Heart defects, an obstruction of the anal opening (imperforate anus), and brain defects such as an absence of the tissue
connecting the left and right halves of the brain (corpus callosum) occur in less than 50 percent of those affected. Facial abnormalities that may be seen in this disorder include a flat nasal bridge, thin upper lip, and low set ears. These features vary among affected individuals, even within the same family.

There are two forms of Opitz G/BBB syndrome, which are distinguished by their genetic causes and patterns of inheritance. The X-linked form of Opitz G/BBB syndrome is caused by a mutation in a specific gene, MID1, on the X chromosome. Autosomal dominant Opitz G/BBB syndrome is caused by a mutation in an as-yet unidentified gene on chromosome 22. The signs and symptoms of the autosomal dominant form of the condition are comparable to those seen in the X-linked form. The X-linked form of Opitz G/BBB syndrome tends to include cleft lip with or without cleft palate, while cleft palate alone is more common in the autosomal dominant form. Females with X-linked Opitz G/BBB syndrome are usually mildly affected, as hypertelorism may be the only sign of the disorder.

X-linked Opitz G/BBB syndrome is thought to affect 1 in 50,000 to 100,000 males. The incidence of autosomal dominant Opitz G/BBB syndrome is unknown. It is part of a larger condition known as 22q11.2 deletion syndrome, which is estimated to affect 1 in 4,000 people.

The autosomal dominant form of Optiz G/BBB syndrome is caused by a deletion in one copy of chromosome 22 in each cell. This condition is considered part of 22q11.2 deletion syndrome because affected people usually have a deletion in the same region of chromosome 22. These cases occur in people with no history of the disorder in their family. It is not yet known which deleted gene(s) cause the signs and symptoms of Opitz G/BBB syndrome.

  • other chromosomal conditions

Other changes in the number or structure of chromosome 22 can have a variety of effects. Mental retardation, delayed development, delayed or absent speech, distinctive facial features, and behavioral problems are common features. Frequent changes to chromosome 22 include an extra piece of the chromosome in each cell (partial trisomy), a missing segment of the chromosome in each cell (partial monosomy), and an abnormal structure called a ring chromosome 22. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure. Rearrangements (translocations) of genetic material between chromosomes can also lead to extra or missing material from chromosome 22. The most common of these translocations involves chromosomes 11 and 22.

Cat-eye syndrome is a rare disorder most often caused by a chromosomal change called an inverted duplicated 22. In people with this condition, each cell has a small extra chromosome made up of genetic material from chromosome 22 that has been abnormally copied (duplicated). The extra genetic material causes the characteristic signs and symptoms of cat-eye syndrome, including an eye abnormality called an iris coloboma (a gap or split in the colored part of the eye), small skin tags or pits in front of the ear, unusually formed ears, heart defects, kidney problems, malformations of the anus, and, in some cases, delayed development.